MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer.
Nat Commun, 2019/05/16;10(1):2197.
Zhan T[1, 2], Ambrosi G[1], Wandmacher AM[1], Rauscher B[1], Betge J[1, 2], Rindtorff N[1], Häussler RS[3], Hinsenkamp I[2], Bamberg L[2], Hessling B[4], Müller-Decker K[5], Erdmann G[6], Burgermeister E[2], Ebert MP[2], Boutros M[7]
Affiliations
PMID: 31097693DOI: 10.1038/s41467-019-09898-0
Impact factor: 17.694
Abstract
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.
MeSH terms
Adenomatous Polyposis Coli Protein; Animals; Antineoplastic Agents; Biopsy; CRISPR-Cas Systems; Carcinogenesis; Cell Line, Tumor; Cell Plasticity; Colorectal Neoplasms; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Intestines; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Neoplastic Stem Cells; Protein Kinase Inhibitors; Proteomics; Wnt Signaling Pathway; Xenograft Model Antitumor Assays; ras Proteins
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